Rapid Palatal Expansion to Treat Nocturnal Enuretic Children: a Systematic Review and Meta-Analysis.

STATEMENT OF THE PROBLEM
Refractory nocturnal enuresis possesses a heavy psychosocial burden for the affected child. Only a 15% spontaneous annual cure rate is reported.


PURPOSE
This patient-level meta-analysis aimed to evaluate the efficacy of rapid palatal expansion to treat nocturnal enuresis among children.


MATERIALS AND METHOD
A sensitive search of electronic databases of PubMed (since 1966), SCOPUS (containing EMBASE, since 1980), Cochrane Central Register of Controlled Trials, CINAHL and EBSCO till Jan 2014 was performed. A set of regular terms was used for searching in data banks except for PubMed, for which medical subject headings (MeSH) keywords were used. Children aged at least six years old at the time of recruitment of either gender who underwent rapid palatal expansion and had attempted any type of pharmacotherapy prior to orthodontic intervention were included.


RESULTS
Six non-randomized clinical trials were found relevant, of which five studies had no control group. Eighty children were investigated with the mean age of 118 (28.12) months ranged from 74 to 185 months. The median time to become completely dry was 2.87 months [confidence interval (CI) 95% 2.07-2.93 months]. After one year, the average rate of becoming complete dry was 31%. The presence of posterior cross bite [relative risk (RR): 0.31, CI 95%: 0.12-0.79] and signs of upper respiratory obstruction during sleep (RR: 5.1, CI 95%: 1.44-18.04) significantly decreased and increased the chance of improvement, respectively. Meanwhile, the other predictors did not significantly predict the outcome after simultaneous adjustment in Cox regression model.


CONCLUSION
Rapid palatal expansion may be considered when other treatment modalities have failed. The 31% rate of cure is promising when compared to the spontaneous cure rate. Though, high-level evidence from the rigorous randomized controlled trials is scarce (Level of evidence: C).


Introduction
Nocturnal enuresis which is defined as involuntary loss of urine after the age of five is not an uncommon problem. About 15% of children are affected at this age. This rate would dramatically decrease to 5% and 1-2% at the ages of 10 and 15 years. [1][2] A report from Iran indicated that 17.5% of first-grade schoolers were affected and similar to the other investigations, it is exceeding more frequent in male patients than the female patients. [3][4][5] Monosymtomatic nocturnal enuresis, the absence of or subtle daytime symptoms, constitutes 80% of cases with nocturnal enuresis. These cases can be classified into either primary (i.e., never achieved longlasting dryness) or secondary (i.e., dryness has been achieved for at least six months before enuresis begins). [6] An annual spontaneous rate of 15% is estimated without any medicopharmacologic intervention. [7] One might note that nocturnal enuresis should not be confused with nocturia, which is the frequent night awakening to void. [8] The aetiology of monosymtomatic enuresis is not clearly understood. [9] Neveus hypothesized that it is mainly a sleep disorder and low arousability, nocturnal polyuria and detrusor hyperactivity are the other contributors to the nocturnal enuresis. Neveus attributed the high arousal threshold of enuretic patients to disturbance of the upper pons. [9] Furthermore, sleep disorders, sleep-disordered breath (SDB), and psychological abnormalities may be the major accompaniers. [10][11][12] Up to 80% of enuretic children have concurrent sleep apnea. [13] Sleep patterns of enuretic and non-enuretic children are the same. [11] Nevertheless, the major problem is associated with the deep sleep and low arousability or high arousal threshold among enuretic children. [9][10][11][12] Nocturnal enuresis could occur in any stage of sleep. Antidiuretic therapy effectively can reduce the wet nights, however, sleep pattern may remain unchanged. [14] It is shown that the severity of nocturnal enuresis and obstructive sleep apnea are correlated. [13]As previously shown, adenotonsillectomy, by reduction of nocturnal resistance airflow, may alleviate enuresis in children with SBD and hypertrophic tonsils. [15] Generally, the proposed treatment modalities are motivational therapy, bladder training, fluid management, night alarms and pharmacological agents such as desmopression and tricyclic antidepressants. Based on most meta-analyses and clinical trials, however, the plateau of evidences is just in favor of night alarms and pharmacotherapy with either oral desmopression or imipramine. [6] Nonetheless, a few percent of enuretic children may remain unresponsive that brings a heavy psycho-social burden for both the child and family. In addition to the standard and accepted modalities, alternative methods such as mandibular advancement and complementary alternative medicine such as eletroacupunture are suggested for refractory enuresis. [16][17] Moreover, there are some promising outcomes regarding the management of such resistant cases implementing an orthodontic device by rapid increasing of maxillary width within 10-14 days (i.e., average five millimeters), so-called rapid palatal expansion (RPE). [18][19][20][21] This technique dates back to 19 th century (1860), when Angel successfully treated posterior crossbite which became more popular with altering popularity and declined in various eras. [22][23] Maxillary bone articulates with 10 other craniofacial bones, hence, maxillary expansion would influence the structures of temporo-mandibular joints (TMJ) and those adjacent nasal and pharyngeal spaces. In addition to the crowding and cross bites, RPE can be applied to improve nasal flow resistance, conductive hearing loss, TMJ dysfunctions and asymmetric position of the condyle. [22,[24][25][26] Notably, increasing the nasal chamber radius by expanding the nasal floor will increase the nasal volume by a power of four (Poiseuille's Law). [25] There is no meta-analysis of existing literature regarding the effect of RPE on children nocturnal enuresis. We opt to perform a meta-analysis of pooled data from previous researches to discover the real efficacy of this unique treatment modality with the increased power of analyses. In addition, the effect of various unmet potential predictors such as age, gender or dento-skeletal morphology may be better explored.  indicator of pre-existing stressor), skeletal Angle's classification (i.e., Angle class I-III dento-skeletal relationship), presence of crossbite (i.e., jaws width discrepancy which leads to circumferential malpositioning of the first permanent molar with regards to its antagonist), average palatal expansion, study methodology, response rates (i.e., responders, partial responders and non-responders), time to become completely dry or improved, follow ups and enuresis type (i.e., primary or secondary) were gathered. Response rate was considered with two binominal modes; complete or partial response versus no response and complete response versus partial or no response. Correlations of dento-skeletal occlusion with triple response categories were first evaluated by means of Gamma ordinal statistics, thereafter two-by-two cross-tabulation was performed between the binominal Angle classes (I vs.

Materials and Method
II, III or II vs. I, III or III vs. I, II) and two beforementioned binominal response categories. These comparisons were reported by either a Pearson Chi-square or Fisher's exact test preceded by a Cochrane's test for the adjustment of nominal confounder. Age variable was first entered as a continuous numeric data. Afterwards, average age obtained from the receive operating characteristic (ROC) curve and a dichotomous age predictor was entered to the model. Also a cut-point of ten was evaluated as previously reported by Schutz-Fransson. [21] We defined severe nocturnal enuresis when the child wet the bed more than four nights a week. Comparisons of wet nights between tripleresponse categories were evaluated with the analysis of variance (ANOVA) which was adjusted with a Browns-Forsythe statistics. Further multiple comparisons were accomplished with a Games-Howell adjustment. Overly, an average was entered when data were displayed with a narrow range of wet nights.

Statistical Methods
The nominal data were expressed with frequencies (%) and the numeric data were shown as mean (standard deviation). Meta-analysis was accomplished applying an individual patient data (IPD) method. Cumulative portions of survival at 12 th month after the beginning of the study were calculated and plotted by the Kaplan-Meier analysis. There was not a common and certain definition for partial response between the studies; hence, complete responders were mainly analyzed against partial and non-responders. A Coxregression model was also built with a forward conditional method to investigate the effect of predictors on treatment outcome and odds ratios were displayed with a two-sided 95% confidence interval (CI). In addition, a further subgroup analysis was carried out to determine whether the effect of variables was influenced by the interaction of the others or not. The mean wet nights/ week was compared before and after RME considering stable responses around six to twelve months after the initiation of orthodontic treatment

Systematic Literature Search
Due to a few existing studies; we extended our inclusion criteria to all types of published and unpublished studies. Moreover, follow up duration of at least 6 months were excluded from the primary exclusion criteria. Six clinical trials were found relevant ( Figure   1, Table 1).
All included studies were case series.   There are controversies considering the improve-  [18][19]26] Nevertheless, Schütz-Fransson and Kurol argued that nocturnal enuresis improvement was irrelevant of such modifications. [21] Rapid palatal expansion increases the maxillary width in a nonparallel wedge-shaped manner, with most increment in the anterior part. This is best explained by anatomic inhibitory effect of sphenoid bones located posteriorly to the palatine bones. [21] However, there is no consensus on which direction it acts most. [29][30] The presence of crossbite was found to have a confounding effect on improvement. It was expected since most attempts were exerted on normalizing the existing deficit instead of over treating the maxilla. In addition, children with posterior cross bite received the least benefit from RPE due to the substantial increase by non-equal widening, which was considerably higher in the anterior part of palate. [22] A considerable portion of enuretic children was found to have concurrent sleep problems which was in agreement with a previous work by Barone et al. [13] With regards to Weirder reports, elimination of airway obstruction at nasopharyngeal or oropharyngeal level with either tonsillectomy or adenoidectomy or both may improve the nocturnal enuresis.  This find- Nevertheless, a child with isolated enlarge tonsils benefits mostly from adeno-tonsillectomy and isolated nasal obstruction demands an orthodontic treatment rather than a surgical approach. This fact may rationalize the heterogeneity of outcomes from various studies. In the present meta-analysis, the number of cases with exact report of such information was too low and further subgroups analyses were not applicable which were unreliable and low-powered. Of included children in current meta-analysis, a considerable portion exhibited improved breath pattern, nasopharyngeal airway dimensions and airflow. [18,20,26,28] Reported by Timms, many children claimed easier nasal breathing after RPE. 18 Six out of ten children in Akhavan Niaki and Farbod investigation changed oral breath to nasal breath. [28] Establishment of a correlation between cessation of nocturnal enuresis and degree and pattern of nasal airflow is still a matter of debate. [19,21] A plenty is still to be known about the effect of concomitant obstructive sleep apnea and im- When failure is deemed in future, a child could be earlier intervened and supported, because increased consequent stresses might prevent from the optimal outcomes even in the non-complex cases. Parental divorce as a psychological confounder was not contributory to the outcome. Previously, Desta et al. [12] reported a higher prevalence of parents' separation among enuretic children. Meanwhile, they were not quite sure about the direction of correlations between the psychopathologies and enuresis. [12] Noteworthy, in contrast to the long lasting belief on the detrimental effect of psychological abnormalities; currently such abnormalities are approached as a result, rather than the cause of nocturnal enuresis. [39] Fields et al. [40] found that the long-and normal-face individuals had similar tidal volume; yet nasal and oral passage did not share the same portion especially in long-face patients, who are mainly oral breathers. [40] Hence, it is probable that the long face patients suffer less from an obstruction located in the nasal cavity and may benefit mostly from the adenotonsillectomy. Different Angle classifications (i.e., I-III) were not different in terms of response rate in our study. Unfortunately, facial morphology was not pro- Capdevila et al. found that higher brain natriuretic peptide is secreted in cases with either obstructive sleep apnea or enuresis. This might be due to the higher venous return and more dilated atrium accompanied by the airway obstruction and increased intra-thoracic negative pressure associated with posing a deep breath against a narrowed or collapsed airway. [43] Importantly, RPE could increase the airflow. [19][20][21] This could improve nasal breathing and blood oxygen saturation. [21] The possible explanation of RPE in improving nocturnal enuresis may be correlated to obstructive sleep apnea. Hence, the latter suggested mechanism may be the corner stone of treatment and should be focused more on upcoming investigations.
Interestingly, sleep-disordered breathing and nocturnal enuresis share many non-orthodontic (e.g., adeno-tonsillectomy) and orthodontic (e.g., rapid palatal expansion) treatment options. [26] Focusing on concomitant obstructive sleep apnea in an affected child may guide the clinician to decide how to prioritize and individualize the treatment options.

Safety of RPE has been recently investigated by
Li et al. [44] They qualified the brain blood supply by means of a dynamic perfusion computed tomography.
They attributed the increased cerebral blood flow and cerebral blood volume to indirect forces of RPE through the circum-maxillary sutures, superior ophthalmic fissure, carotid sulcus, and foramen lacerum with subsequent vasodilatation of inner vasculature. [44] The child should be least six years old. This cut off point is warranted since urinary incontinent is not considered pathologic in a younger child and RPE can damage the naso-maxillary complex and make nasal deformity in younger preschoolers and toddlers. [45]

Strengths, Limitations and Future Direction
The current meta-analysis is a patient-level one with the individual patient data (IPD) method. To our knowledge, it is the first meta-analysis to assess the effect of rapid palatal expansion on nocturnal enuretic children. Individual patient data method has the advantages of higher final power and the ability to test the new hypotheses for casual relationships between the different variables of studies. [46] Also, this method enables the investigator to modify the confounding effects of some variables on the outcome, especially when such confounders were not considered in the original articles.
Moreover, aggregation bias is lessened, by which groups' results cannot be confidentially associated to a particular patient. Nevertheless, the main disadvantage of this method is inability to access all detailed data. [46] As presented before, data from included studies showed substantial heterogeneity. The analyses exe- As another limitation, our analyses suffered from a right-censoring due to heterogeneous durations of follow ups. Our suggestions for the future works may be addressed to more powered randomized controlled trials with adequate sample size and treatment arms, and also concurrent polysomnographic study with special attention to the brainstem and ascending reticular arousal system (ARAS) activity and 3-combined maxillary expansion and mandibular advancement.

Conclusion
In conclusion, rapid palatal expansion increases the chance of improvement by 2.06-fold when compared to 15% annual spontaneous improvement rate. The presence of posterior cross bite (relative risk: 0.31) and signs of upper respiratory obstruction during sleep (relative risk: 5.1) significantly decreased and increased the chance of improvement, respectively. The younger the children (<105 months), the higher the success rate after rapid palatal expansion (odd ratio:

3.37).
Rapid palatal expansion to treat nocturnal enuresis can only be suggested when pharmacologic medication and nigh alarm are being attempted with no remarkable outcome. Importantly, refractory enuretic children should be checked for concurrent presence of obesity and obstructive sleep apnea. [43] By this age, the child can play an active role through the treatment.
Indeed, any treatment modality may be efficient when accompanied by child's willingness. It is noteworthy to mention that the current level of evidences lack enough support to recommend such alternative method to treat nocturnal enuretic children; hence, it can be suggested when other interventions have failed (Level of evidence: C).